Toxicology Flashcards
What is enterohepatic recirculation?
Occurs when a toxin is excreted form the liver, via bile, which is then deposited in SI where it can be reabsorbed, sometimes repeatedly, extending its toxic effects
What is P glycoprotein?
A drug transporter on the luminal surface of brain capillaries, responsible for transport of substances from the brain tissue back into capillary lumen, limiting brain exposure to drugs and toxins
What population may have an undeveloped BBB?
Young animals
How does MDR1 play into the BBB?
- MRD1 controls P glycoprotein
- Certain breeds of dogs lack full expression of the gene and are susceptible to toxic brain exposure to drugs at normal therapeutic doses
Dermal decontamination of a patient should be done with (dishwashing/dishwasher) soap
Dishwashing
What type of substances can be readily absorbed via the dermis?
Lipophilic substances
Why are alkaline agents more destructive to the eye?
They cause a liquefactive necrosis which results in transformation of tissue into a liquid viscous mass that can damage deeper layers
Why do acidic agents not cause as much damage as alkaline agents (to the eye)?
They do not penetrate tissues as well and self limit due to precipitation of epithelial proteins
How should of ingestion of corrosive substances be treated?
- Rapid dilution with water or milk
- Emesis CONTRAINDICATED because it can re-expose the oral tissues to the caustic agent, leading to significant damage
In what species is emesis contraindicated?
- Rabbits and rodents
- Weak stomachs and lack the natural ability to vomit?
Why is syrup of ipecac no longer recommended as an emetic agent?
Carries a risk of cardiotoxicity, HGE, skeletal muscle weakness
Why is hydrogen peroxide not recommended as an emetic agent in cats?
Can cause refractory vomiting
How does apomorphine exert its effect?
It is a dopaminergic agonist - its stimulates dopamine receptors in the CRTZ which activates the VC
What drug can be used to treat the sedation caused by apomorphine?
Naloxone - it will reverse the sedation but not the emesis
When is gastric lavage most effective?
<4 hours post ingestion
What substances does AC not bind to?
- Strong acids/alkalis
- Alcohols (ethanol/methanol)
- Cyanide
- Lithium
- Ethylene glycol
- Metal (iron)
- Bleach
- Xylitol
Why do electrolytes need to be monitored with giving multiple doses of AC?
It has strong osmotic properties that can create serious imbalances
What is cholestyramine?
- Bile acid sequestrant
- Binds bile in the GIT to prevent its reabsorption
- Strong ion exchange resin –> exchanges Cl anions with anionic bile acids in GIT and binds them strongly in resin matrix for elimination
What is ion trapping?
- It increases the excretion rate of toxic drugs
- Most drugs are weak acids or weak bases
- Drugs typically are unable to pass through cell membranes unless they are in a non ionized state
- Weak acid drugs are absorbed best when placed in an acidic environment as they will be in a non ionized stated
- Weak base drugs are absorbed best when placed in an alkaline env
- By modifying pH of a surrounding env, we can modify ionization trap a drug, and prevent its absorption
- Technique used for drugs that are readily absorbed in kidney’s nephron or bladder
What is the lipid sink theory?
- Provides a “sink” where fat soluble toxins can be bound and excreted without being metabolized
- ILE expands intravascular lipid phase which sequesters lipophilic toxins within it, reducing effect site concentration and toxicity until compound is metaboilized and excreted
- Sink is not selective and will also absorb therapeutic drugs
- Permethrins, baclofen, some antidepressants, bupivicaine, moxidectin, NSAIDs, Ca channel blockers, beta blockers, avermectins, cannabis, amphetamines,
What is NAPQI?
- A highly reactive toxic metabolite
- Causes severe oxidative damage to RBC by causing oxidation of Hb to metHb, which does not carry oxygen
What is the toxic dose of acetaminophen for cats?
10mg/kg
What is the toxic dose of acetaminophen for dogs?
75mg/kg
What eye condition can be seen in toxic of acetaminophen?
KCS
How does acetaminophen cause toxicity?
- Metabolized by the liver via sulfation & glucoronidation
- Major pathway converts acetaminophen to inactivate metabolites through conjugation to inactive glucuronide and sulfate metabolites
- Minor pathway metabolizes a/m by the P450 mixed function oxidase to NAPQI
- In normal circumstances, this minor route produces little NAPQI, but in toxicity, the glucuronidation pathway becomes saturated
- In normal circumstances, glutathione detoxifies NAPQI, but in toxicity, glutathione stores quickly become depleted, leaving NAPQI free to bind to lipids in the hepatocyte membrane and causing hepatocellular necrosis
How does NAC act as an antidote for a/m toxicity?
- Provides a substrate for glutathione, allowing inactivation of toxic metabolites
- Repeated doses due to enterohepatic recirculation
Why are CYP 450 inhibitors contraindicated as treatment for acetaminophen toxicity in cats?
Cats utilize the CYP pathway to convert methemoglobin to Hb
What are some treatments for acetaminophen toxicity?
- NAC
- Cytochrome P450 inhibitors (cimetidine, ranitidine - slow metabolism of acetaminophen)
- Ascorbic acid (used for methemoglobinemia in affected cats
- Feed cats kitten food due to increased sulfhydryl group substrates
How can most adhesives be removed?
With vegetable oil, which can then be washed off with dishwashing soap
What is the toxic component of alliums?
- Propyl disulfide
- Metabolism produces oxygen free radicals
- Erythrocytes are sensitive to oxidative injury
- Disulfides denature Hb, which forms Heinz bodies, which are then removed from circulation via hemolysis
In what form are alliums toxic?
- All toxic regardless of whether it is raw, cooked, or dehydrated
- Dehydrated will cause signs at lower doses than raw
- Cats fed baby food with as little as 0.3% onion powder can become affected
What is amitraz?
- An alpha 1 & 2 adrenergic agonist applied topically to control ticks, mites, lice. Affects a1 & a2 adrenergic receptors in CV system
- Cats are highly sensitive to its effects
- Hyperglycemia common
- Avoid atropine even in face of bradycardia - likely to produce significant tachycardia
Are ant traps toxic?
Some contain arsenic but have low concentrations of toxins and are a very small size - likely no problem of toxicity, risk of FB is higher
How do anticoagulant rodenticides work?
- By antagonizing Vit K epoxide reductase, preventing the activation of clotting factors II, VII, IX, X. Depletion of these factors slows all coagulation pathways
Why is PT the first to show an issue?
F VII only has a half life of 6 hours
How long do 1st generation rodenticides depress clotting factors?
7-10 days, -farins
How long do 2nd generation rodenticides depress clotting factors?
3-4 weeks, - coums
Enterohepatic recirculation can occur with which anticoagulant rodenticide?
Brodifacoum
How long will it take for Vit K to start restoring new clotting factors?
12-24 hours
What are the 4 main groups of antidepressants?
- MAOI inhibitors
- Tricyclics
- SSRIs
- Atypical
How do MAOIs work?
- Monoamine oxidase is an enzyme that breaks down norepi, epi, dopamine, and serotonin
- When enzyme is inhibited, the levels of these neurotransmitters increase
- Hypo or hypertension, CNS depression, arrythmias, coma, death
How do tricyclics work?
- Block reuptake of norepi and serotonin, increasing their levels
- Produces similar signs as MAOI
How do atypicals work?
- Cause levels of serotonin, norepi, and dopamine to increase
What is serotonin syndrome?
- Results from excess serotonergic antagonism of serotonin receptors in the CNS & PNS
- Causes mental status changes, neuromuscular abnormalities and autonomic instability
- Patients present lethargy, which progresses to agitation
- Thermoregulatory center frequent reset - present hyperthermic
- Tremors, seizues
What is the treatment for serotonin syndrome?
- Emesis
- AC
- Phenothiazines are serotonin antagonists
- Cyproheptadine is a nonspecific serotonin antagonist
- Propranolol is a serotonin receptor antagonist
What drugs can cause serotonin syndrome?
- Amantadine
- Bupropion
- Carbamazepine
- Codeine
- Tramadol
What is the toxic component of autumn crocus and how does it exert its effect?
- Colchicines and other alkaloids
- Toxin arrests mitosis, leading to apoptosis/cell death
- Particular threat to felines
Which toxicity can cause a flaccid paralysis?
Avermectins
How do avermectins exert their effect?
- GABA agonism; hyperpolarizes cell membranes and prevents neuronal depolarization, leading to flaccid paralysis
- MRD1 dogs can show toxicity at lwoer levels
- Works by inhibiting Cl channels
- In vertebrates at high enough doses, can overwhelm the BBB and enter CNS
- Toxicity often occurs from dogs receiving LA doses, or eating feces of LA
- Often combined with spinosad, an antiparasitic, which lowers the toxicity threshold for ivermectin by permitting more to remain in the CNS
What are the toxic doses for avermectins?
- Dogs: 2.5mg/kg
- Cats: 1.3mg/kg
- Sensitive dogs: 100-500mcg/kg
- Young dogs: 300mcg/kg
What is the treatment for avermectin toxicity?
- Decontamination and supportive care
- Undergoes enterohepatic recirculation
- Lipid soluble toxin
Should emesis be performed in cases of ingestion of bleach and household cleaners?
No
What is bromethalin and how does it exert its effect?
- A non anticoagulant rodenticide made to kill warfarin resistant rats
- Works by uncoupling of oxidative phosphorylation in the CNS & liver mitochondria
- This causes a decrease in ATP production and then causes ATP dependent transport pumps to not function
- This results in the loss of ability to maintain osmotic gradient and membrane potential into cell
- This leads to a build up of intracellular Na that causes water to move into cells and they swell with water
- Na influx into brain cells causes cerebral edema and loss of function
- CNS signs occur from increased ICP due to fluid shift
What are bromethalin toxicity signs classified as?
- Paralytic or convulsant (dose dependent)
- Paralytic = amount ingested greater than lethal dose but less than LD50
- Convulsant = amount ingested is greater than LD50
- Final stages of toxicity may be decerebrate posture
- Cats paralytic regardless of dose
How many cannabinoid receptors do dogs and humans have?
2, CB1 (primarily in CNS and responsible for most clinical effects), and CB2 (peripheral tissues)
Does THC undergo enterohepatic recirculation?
Yes, and has a long half life due to lipid solubility
Carbamates
- Found in dusts, shampoos, flea and tick collars
- Cause nearly identical toxicity to organophosphates, except that it is a REVERSIBLE inhibition of cholinesterase activity
What plants are cardiac glycosides?
Kalanchoe spp
- Foxglove
- Lily of the valley
- Oleander
- Laurel
- Dogbane
- Some milkweeds
How do cardiac glycoside plants exert their effects?
- Inhibit sodium/potassium ATPase
- K accumulates outside cell, preventing Ca release
- Intracellular Na increases and K levels decrease
- Increased Na can be exchanged for Ca, which improves contractility and is how digoxin works as a positive inotrope
- Very small therapeutic window, with too much, there is a progressive decrease of electrical conductivity
- This causes frequent and irregular depolarization of cells
- Result is disorganized cardiac electrical activity, manifesting in cardiac arrhythmias and possible arrest
Do cardiac glycosides undergo enterohepatic recirculation?
Yes
